There are still no effective treatments for neurodegenerative diseases, including Parkinson?s disease (PD), Alzheimer?s disease (AD) and Alzheimer?s related dementias (ADRD). One major obstacle in finding small molecules capable of combatting these synucleinopathies and tauopathies is that the proteins that mediate these disorders are structurally unfolded (i.e. intrinsically disordered). In addition to their tendency to aggregate upon accumulation, intrinsically disordered proteins lack defined binding pockets, thus they have largely evaded traditional drug discovery design efforts. However, recent studies found that enhancing proteasome activity can prevent toxic accumulation of intrinsically disordered proteins (such as ?-synuclein and tau species), reduce brain damage and prevent AD related dementia. Of the different proteasome complexes, only the 20S proteasome targets intrinsically disordered directly for degradation. Unfortunately, the translational exploration of this entirely new therapeutic strategy has been limited due to (1) the lack of a suitable cellular assay to identify 20S proteasome enhancers and subsequently, (2) lack of drug-like small molecule 20S proteasome enhancers. This grant will directly address these two voids that currently prevent the exploration of this new therapeutic strategy to treat PD, AD and ADRDs. In the R61 phase, we will develop and validate the first cellular and physiologically relevant high throughput screening (HTS) assays with the goal to broaden the portfolio of small molecule drug-like enhancers of the 20S proteasome. In the R33 phase, we will optimize the efficacy and physiochemical properties of two select series from that screen to generate the first suitable agents for the translational exploration of this new approach. Successful completion of this work will provide a robust platform to identify and develop suitable drug-like candidates to explore the translational potential of this new therapeutic approach for treating Parkinson?s disease, Alzheimer?s disease and Alzheimer? related dementias.